ASTHMA

CASE STUDY ON ASTHMA

DEFINITION Asthma is a chronic inflammatory disease associated with airway Hyperresponsivenss that leads to recurrent attacks of breathlessness, chest tightness, coughing and wheezing, which vary in severity and frequency from person to person. CARDINAL PATHOLOGICAL FEATURES OF ASTHMA 1. Air Flow Limitation 2. Airway Hyperresponsivenss 3. Airway Inflammation EPIDEMIOLOGY According to World Health Organization (WHO) estimates, 300 million people suffer from asthma and 255000 people died of asthma in 2005. Asthma is the most common chronic disease among children. It is not just a public health problem for high income countries: it occurs in all countries regardless of level of development. Over 80% of asthma deaths occur in low and lower-middle income countries. Asthma deaths will increase by almost 20% in the next 10 years if urgent action is not taken. Asthma is under-diagnosed and under-treated, creating a substantial burden to individuals and families and possibly restricting individuals activities for a lifetime. ETIOLOGY Genetic factors account for 35-75% of the susceptibility. Environmental risk factors for the development of asthma include socio-economic status, family size, exposure to tobacco smoke in infancy and in uterus, allergen exposure, urbanization and decreased exposure to produce an alteration in the immune response system. Risk factor for early recurrent wheezing associated with viral infections includes low birth weight, male gender and parental smoking. Atopy is the predominant risk factor for children to have continued asthma. Environmental exposure is the most important precipitants of severe asthma exacerbations. Viral respiratory tract infections remain the single most significant precipitant of severe asthma.

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ASTHMA LIST OF AGENTS AND EVENTS TRIGGERING ASTHMA Respiratory infections: Respiratory Synsytial Virus (RSV), rhinovirus, influenza, parainfluenza, mycoplasma pneumonia viruses. Allergens : air borne pollens (grass, trees and weeds), house dust mites, animal danders, cockroaches and fungal spores Environment : cold air, fog, ozone, sulphur dioxide, nitrogen dioxide, tobacco smoke, wood smoke Emotions : anxiety, stress and laughter Exercise : particularly in cold, dry climate Drugs/Preservatives : aspirin, NSAIDs, Sulfates, Benzalkonium chloride, beta blockers Occupational Stimuli : bakers (flour dust), farmers (hay mold), spice and enzyme workers, ethylene-diamine, toluene-diisocynate, polyvinyl chloride, plastic, rubber and wood workers (formaldehyde, anhydride) THE IMMUNE SYSTEM OF RESPIRATORY TRACT The three main systems of the immune system are antibodies, inflammatory cells and inflammatory mediators. ANTIBODIES The primary job of antibodies is to bind to an infectious agent and, in so doing, to notify and trigger the rest of the immune system to fight off this invader. Antibodies are created and secreted by B cells. Each individual B cell responds to a unique antigenic structure by secreting an antibody that corresponds to that structure. Once a foreign antigen interacts by binding to the B cell bearing the antibody with best fit, that B cell is activated to divide repeatedly (termed B cell proliferation). The body manufactures 5 classes of antibodies, namely IgM, IgG, IgA, IgD and IgE. IMMUNOGLOBULIN E The antibody class of allergic diseases, including allergic asthma is IgE. It is fundamental to the allergic immune response. Any true allergic reactions occur because IgE antibodies are binding specifically to the substance that is stimulating the allergic reaction. An antigen that stimulates an IgE antibody response is more specifically termed as an allergen. These IgE antibodies are generally directed against substances that are not harmful to the body, including pollens, fur from cats, certain mold spores, certain foods etc.

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ASTHMA More important than the level of circulating IgE is the level of IgE that is bound to the surface of certain inflammatory cells that are central to an allergic reaction. The most important of these cells is an immediate hypersensitivity reaction is the mast cell. After initial exposure of the patient to an allergen, the primary immune response is to generate unique IgE antibodies that become bound to the surface of mast cells. These mast cells live within various tissues of the body, including in the bronchi. If the patient is later re-exposed to an allergen by inhalation, the allergen binds to the surface-bound of IgE on mast cells in the bronchi. Binding of at least two IgE molecules, bridged by a single allergen molecule, is termed cross-linking. Cross linking of IgE by allergen on the surface of the mast cell is the initial biologic event of an allergic reaction. INFLAMMATORY CELLS Participants in the immune system include several types of cells including granulocytes and lymphocytes. The most important granulocytes in asthma are mast cells and Eosinophils. Lymphocytes lack granules and manufacture other kinds of proteins that are involved in the inflammatory process. MAST CELLS A mast cell becomes sensitized to an allergen when the IgE specific for that allergen circulates in the blood stream and eventually lands on the surface of the mast cell; the latter is fixed in a particular tissue location (eg. A bronchial wall). Cross linking of surface IgE by an allergen molecule triggers a rapid activation (<15 minutes) of the mast cell, which then releases numerous inflammatory mediators into the tissue surrounding the cell. EOSINOPHILS The Eosinophils is the inflammatory cell most closely associated with asthma, in association with asthma, elevated number of eosinophils have been identified in various tissue compartments, including: Circulating in the peripheral blood Biopsies of lung tissue, particularly in the bronchial wall of patients with asthma. Fluid specimens obtained from the lung using a bronchoscope In secretions or sputum of asthma

In asthma, eosinophils move from the blood into the bronchi and onto surface of the airway lining. Importantly, the level of eosinophils in each of these compartments demonstrates a rough correlation with the disease state of asthma and even with the clinical severity of asthma. When activated, eosinophils release several pre-formed mediators from within their granules. These granules contain several proteins, among which is eosinophilic cationic protein.

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ASTHMA LYMPHOCYTES B lymphocytes have the important function of manufacturing antibodies. T lymphocytes play an essential role in events that lead to airway inflammation by orchestrating the entire inflammatory response. T cells release a variety of cytokines that communicate with most other cells in the inflammatory process. Cytokines form T cells can, for instance, activate B cells to make antibodies or activate eosinophils versus neutrophils. They are however not a source of mediators of hypersensitivity reactions and thus do not participate in the acute (<15minutes) response to allergen that can cause an acute asthma attack. INFLAMMATORY MEDIATORS The immunologic cascade and the ensuing inflammatory reaction comprise activation of specific inflammatory cells that also release various inflammatory mediators, such as histamine, mast cell tryptase, leukotrienes, prostaglandins, eosinophil cationic protein and cytokines. However these represent a small subset of the several inflammatory mediators that have been identified. PATHOPHYSIOLOGY 1. AIRWAY INFLAMMATION Infectious agents constantly enter the body via the respiratory system. The bronchi have several protective methods against these invaders. These include: Recruitment of inflammatory cells from the blood stream into the bronchial wall, where they directly attack the invading organisms and secrete inflammatory chemicals that are toxic to the organisms Swelling of the bronchial wall Mucus secretion Constriction of the airway

Airway inflammation in asthma is: A direct response of the immune system to a trigger A cascade of immunologic events that includes inflammatory cells and mediators An immune-mediated process that leads to inflammatory changes in the airway, including eosinophil recruitment and airway edema.

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ASTHMA PATHOPHYSIOLOGY OF THE AIRWAY IN ASTHMA In normal individuals, the lumen is free of significant mucus. The single layer of ciliated epithelial cell lines and protects the bronchial wall. The mucous glad provides a protective layer of mucus above the epithelial cells. There are few eosinophils in the bronchial wall. In asthmatics, plasma leakage from blood vessels contributes to bronchial wall edema, which results in thickening of the bronchial wall. Eosinophils migrate from the blood stream into the bronchial wall and the airway lumen and can release eosinophil cationic protein and leukotrienes. Enlarged mucus glands secrete excess mucus that can plug the airway lumen.

2. BRONCHIAL HYPER-REACTIVITY Hyper-reactivity of the airways to several stimuli is a hallmark of clinical asthma, and it appears Bronchial Hyper-Reactivity (BHR) is caused by airway inflammation. Clinically the degree of BHR has been shown to correlate with general asthma severity. The degree of BHR appears to decrease when asthma is well controlled with medication. The ultimate result and significance of BHR is the airflow obstruction that occurs when an asthmatic is exposed to a trigger. 3. BRONCHOCONSTRICTION After this bronchial allergen challenge, there is a rapid decline in Forced Expiratory Volume in One second (FEVI) that begins within 15minutes and generally subsides within the first hour. This bronchial manifestation of immediate hypersensitivity has been termed an early asthmatic reaction (EAR), or the early phase response. After this phase resolve the FEV1 reaches a level that is at or close to the pre-challenge baseline In about 50% of patients, there can be a spontaneous return of bronchoconstriction that occurs several hours after the allergen challenge. This late phase response usually occurs 6-24 hours after exposure to the allergen and is termed the Late Asthmatic Response. This late decline in FEV1 may be less severe than during the EAR but is generally more prolonged, lasting several hours The EAR results from binding of inhaled allergen to mast cell membrane-bound IgE with subsequent release of mediators. Among these mediators, the cysteinyl leukotrienes appear to account for a significant part of the early bronchoconstriction response. The LAR often resembles asthma, which is a chronic inflammatory disease. It is possible that repeated or prolonged episodes of LAR may approximate those events in the airways in both chronic allergic and non allergic asthma.

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ASTHMA 4. AIRWAY REMODELLING The term airway remodeling is widely used to refer to the development of specific structural changes in the airway wall in asthma accompanying long-standing and severe airway inflammation. Airway remodeling and fibrosis may be the cause of fixed airflow obstruction in asthma that is not reversible with steroids, bronchodilators or both. Airway remodeling is characterized by subepithelial collagen deposition, myofibroblast accumulation, airway smooth muscle hyperplasia and hypertrophy, mucus gland and goblet cell hyperplasia and epithelial disruption.

CLINICAL FEATURES SYMPTOMS Cough, wheezing and dyspnea. Asthma symptoms may be circadian, worse at nights and early morning, because the small decrease in airway diameter that occurs normally during these times is exaggerated in patients with asthma. Breathlessness increases when asthma is exacerbated, such as in the presence of allergens, cold air and exercise. Cough is another symptom of asthma (especially in children) and may even be the sole presenting symptom. Wheezing is also a characteristic feature of asthma. Two important indications to worsening asthma are increased nocturnal or early morning awakenings due to asthma symptoms and increased use of bronchodilators.

SIGNS Physical examination of the respiratory system may reveal no apparent abnormality if a patient is not experiencing an asthma attack. During an asthma attack, contraction of the bronchial smooth muscle, edema and increased mucus secretion narrow or closed small airways, resulting in the inability to exhale completely and increased work of breathing in these patients. Wheezing predominantly occurs on exhalation. However it may be absent in severe asthma attacks due to marked limitation of air flow.

LABORATORY EVALUATION PULMONARY FUNCTION TESTS Pulmonary function tests (PFTs) provide a direct assessment of the degree of airflow limitation. Also, by measuring the variability of this measurement, PFTs provide an indirect assessment of Bronchial Hyper Responsiveness (BHR). Abnormalities of lung function may exist even if a patient is asymptomatic.

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ASTHMA SPIROMETRY Spirometry remains the best test in patients suspected of having asthma. Because asthma is an obstructive airway disease, a decrease in the absolute value and percent predicted of the FEV1 to less than 80% of predicted normal may be present. However in mild decrease, FEV1 can be normal. The airflow limitation is considered significantly reversible or responsive when the FEV1 improves by at least 12% and by 200ml (in adults) following an inhaled bronchodilator. In addition to FEV, the ratio of FEV1 to FVC ratio is often below 70% in patients with asthma, and the forced expiratory flow that occurs from 25-75% of FVC (FEF25-75) is considered to measure airway obstruction. It is possible that in chronic severe asthma, the airway obstruction may become "fixed" or "irreversible" due to airway remodeling and fibrosis, in which case there is little or no response to bronchodilators. If a patient has normal air flow when assessed between attacks. Proactive testing with a substance that causes airway narrowing (eg. a methacholine challenge test) may be conducted. In patients with BHR, the provocative concentration of methacholine needed to lower FEV1 by 20% (PC20) is lower than in normal individuals. PEAK EXPIRATORY FLOW RATE Peak flow monitoring can also be used for short-term monitoring, to manage exacerbations, and for daily long-term monitoring. Patients, who have PEFR measurements consistently less than 80% of their best effort, may need additional medications to control their asthma. A PEFR of less than 50% of best effort indicates a severe exacerbation of asthma. SKIN TESTS Many patients with asthma are atopic, and their reaction to a wide range of external allergens can be a common exacerbating factor of asthma. A drop of each allergen solution is distributed on the forearm and a needle introduced through the drop into the skin surface to a depth of about 1mm. The patient's skin reaction at the site, if any, is assessed 15-20 minutes later. A positive wheal and flare reaction indicates that specific immunoglobulin E (IgE) antibodies to that particular allergen arc bound to mast cells in the skin. BLOOD TESTS The measurement of allergen-specific IgE in the scrum is determined using RadioAllergoSorbent Test (RAST). A positive test does not guarantee that the patient is allergic because an individual can have elevated allergen-specific IgE that circulates in the blood without having clinical symptoms associated with actual exposure to that allergen

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ASTHMA PERIPHERAL BLOOD EOSINOPHILS An elevation in the peripheral blood eosinophil count can be an indicator of inflammation that is allergic in nature. RADIOLOGY TESTS The chest X-ray of a patient with asthma is often normal. However hyperinflation of the lungs may be observed in acute exacerbations. TREATMENT Treatment should be directed towards reducing inflammation and increasing bronchodilation. Other measures such as avoidance of recognized trigger factors, may also contribute to the control of this disease. CHRONIC ATTACK The pharmacological management of asthma depends upon the frequency and severity of patient symptoms. Infrequent attacks can be managed by treating each attack when it occurs, but with more frequent attacks, preventive therapy need to be used. The preferred route is by inhalation. This allows the drug to be delivered directly to the airways in smaller doses and with fewer side effects. They have faster onset of action and give better protection from bronchoconstriction. Treatment of chronic asthma is usually given in a stepwise manner as described below Step 1 Occasional use of inhaled short acting 2 adrenoreceptor agonist bronchodilators. Short acting bronchodilators such as salbutamol or terbutaline are used by inhalation as required. If the patient is using 2 agonist more than once daily, move to step 2. Salbutamol inhaled adults 100-800mcg in 3-4 divided doses. It is a direct-acting sympathomimetic agent which demonstrates relatively selective action on beta-2 adrenergic receptors. Adverse reactions: angina, hypotension, nausea, vomiting, pharyngitis. Step 2 Regular inhaled anti-inflammatory agents. Inhaled short acting 2 agonists are used as required and the patient is commenced on regular inhaled steroid (beclomethasone, budesonide or fluticazone) up to 800mcg daily. This corticosteroid exerts its antiinflammatory effect by inhibiting both inflammatory cells and release of inflammatory mediators. Administered as an inhalation, it may work topically in the bronchial tree at the sight of deposition and few adverse effects can be Headache, Candidiasis, and Nasopharyngeal irritation

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ASTHMA Alternatively, sodium chromoglycate or nedocromil sodium can be used. 1 to 2 drops in each eye twice daily. Nedocromil sodium is an anti-inflammatory agent that blocks the release of mediators of hypersensitivity reactions from mast cells, eosinophils, neutrophils, macrophages, monocytes and platelets. The drug inhibits the release of histamine from mast cells and beta-glucuronidase from macrophages in bronchoalveolar cells. It does not exert any bronchodilating, antihistaminic, or corticosteroid effects .Adverse effects: Bad taste in mouth, Nausea, Vomiting, Dizziness, and Headache

Step 3 High dose of inhaled steroid or low doses of inhaled steroids plus long acting inhaled 2 agonist. Inhaled short acting 2 agonists are used as required plus an inhaled corticosteroid in the dose range 800-2000mcg daily. When corticosteroids are inhaled in high dose the use of large volume spacer is recommended. When powder inhalers are used, mouth rising and gargling are encouraged.

Step 4 High doses of inhaled steroid and regular bronchodilators. Inhaled short acting 2 agonists are used to require with an inhaled corticosteroid (80-2000 mcg daily)plus a sequential therapeutic trial of one or more of Inhaled long acting 2 agonist

Leukotrienes receptor antagonist (montelukast 10mg, zafirlukast 20-40mg daily). Mechanism of action: binds to cysteinyl leukotrienes (CysLT) type-1 receptors found in human airway (smooth muscle cells and macrophages), which prevents airway edema, smooth muscle contraction and other respiratory inflammation. Adverse effects: Headache, Allergic granulomatosis angiitis inhaled ipratropium bromide or oxitropium bromide (2 to 3 puffs every 6 hr). Ipratropiumbromide is a cholinergic antagonist of acetylcholine at the cholinergic receptors. It suppresses the increase of cyclic guanosine monophosphate (cyclic GMP) levels due to the interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle Adverse reactions: Abnormal taste in mouth, Bronchitis , Sinusitis

long acting 2 agonists high doses of inhaled 2 agonists Sodium chromoglycate or nedocromil sodium the role of anti IgE antibody therapy is under evaluation.

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ASTHMA Step 5 Addition of oral corticosteroid therapy Step 4 treatments are given plus regular prednisolone tablets prescribed in the lowest necessary amount. ) 40 to 80 mg/day ORALLY in 1 or 2 divided doses until PEF reaches 70% of predicted or personal best; outpatient burst, 40 to 60 mg ORALLY in 1 or 2 divided doses for a total of 3-10 days . Adverse effects: Body fluid retention, Hypertension. Review treatment every 3-6 months. If control is achieved a step wise reduction in treatment may be possible

SHORT COURSE ORAL CORTICOSTEROID TREATMENT If it is often required to regain control of symptoms. For adults 30-60mg of prednisolone can be given initially and the same dose continued in single daily dose each morning until 2 days after control is established. In children the dose is 1-2mg/kg. Increase in dose of inhaled corticosteroid. Doubling the dose of inhaled corticosteroids is often advised to control minor exacerbation of asthma. MANAGEMENT OF ACUTE SEVERE ASTHMA The aims of management are to prevent death, to restore pulmonary function and to prevent early relapse. IMMEDIATE TREATMENT OXYGEN: Oxygen should be given at the highest concentration available (usually 60%), thereafter the concentration of oxygen used can be adjusted according to the arterial blood gas measures. HIGH DOSE OF 2 AGONISTS When possible the patient should be mobilized using oxygen salbutamol 2.5-5 mg or terbutaline 5-10 mg should be given initially and repeated within 30 minutes if necessary. An alternative method of giving high doses of 2 agonists is to use a large volume spacer device. SYSTEMIC CORTICOSTEROIDS They are necessary in all cases of acute severe asthma. Oral prednisolone 30-60mg should be given initially

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ASTHMA CONTINUED MANAGEMENT OF ACUTE SEVERE ASTHMA If features of severity persists, Ipratropium bromide0.5mg should be added to the nebulised 2 agonists Continue 2 agonists treatment every 15-30 minutes as necessary. Reduce 4 hourly, once clear clinical responses. Mechanical ventilation

PEAK FLOW METER A peak flow meter is a small, hand-held device used to monitor a persons ability to breathe out air. It measures the airflow through the bronchi and thus the degree of obstruction in the airways. A peak flow meter measures the patient's maximum speed of expiration. Or Peak Expiratory Flow Rate (PEER or PEF). Peak flow readings are higher when patients are well and lower when the airways are constricted. From changes in recorded values, patients and doctors may determine lung functionally, severity of asthma symptoms and treatment options. PATIENT EDUCATION Patient education should begin at the time of diagnosis and be revised at every subsequent consultation. Education involves the patients understanding about the nature of asthma, the practical skill necessary to manage asthma successfully and the appropriate action in response to deteriorating asthma. It is important for the patient to understand the difference between reliever (bronchodilator) and preventer (anti inflammatory) medications and patients should be fully capable of using their inhaler devices. Use of a peak flow meter provides patients with an objective measure of airway obstruction and allows them to monitor the effect of treatment and severity of exacerbations. Educate patients about asthma medications. Instruct patients about the proper techniques for inhaling medications. Monitor medication use and refill intervals to help identify patients with poorly controlled asthma. Encourage patients purchasing OTC asthma inhalers or tablets to seek medical care Help patients use peak flow meters appropriately. Help patients discharged from the hospital understand their asthma management plan

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ASTHMA

REFERENCES 1. Pharmacotherapy- A Pathophysiological Approach-JosephT.Dipiro-7thEdition. Page.no.463-494 2. Harrisons Principles of Internal medicine-Harisson-16th edition. Page.no.-1508-1515 3. Pharmacotherapeutics and Clinical pharmacy-Roger Walker. - 7th edition. Page no. - 367-385

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